The World Health Organization (WHO) warns that in the world there are more than 1,600 million people with overweight and that number increases exponentially. Also according to the WHO, the number of obese people is more than 700 million.
Previously, it was considered that overweight or obesity were problems that only affected rich countries but the WHO estimates show that overweight and obesity are increasing exponentially in the low and middle income countries. This is due to several factors such as the widespread change of diet towards increased intake of calories, fats, salts and sugars, the trend towards the decrease of physical activity caused by the sedentary nature of the job, changing transportation media and the increase of urbanization.
In Mexico, according to official data, 70% of adults are overweight and even worse, the same percentage is recorded in children between 5 and 11 years old (4.5 million children). The care of people suffering from obesity in Mexico has grown considerably in recent years, in more than 60% since 2000, triplicating the percentage since 1980.
Obesity is a chronic and degenerative disease. In adults, overweight and obesity promote the development of diseases such as hypertension, diabetes mellitus, gout, stroke, heart disease and more. Some scientific research assure that the current childhood obesity will cause, in the coming years, further grow of the population of young adults with diabetes mellitus, hypertension, hyperlipidemia and many other problems related to excess body fat and sedentary lifestyles.
In the case of cardiovascular diseases, it has been observed that the risk of developing coronary disease increases by 20% in overweight people and 50% in obese people.
The risk of developing type 2 diabetes increases by 20% in overweight or obese people.
On the other hand, a body mass index (normal BMI 18.5-24.9) equal or greater than 25 is associated with a higher risk of suffering bone and hip fractures.
Compared with normal weight individuals, those who are overweight and obese have a higher risk of developing asthma and kidney diseases.
Nowadays there are different medications and remedies for the treatment of overweight and obesity, however, to date, there remains a need for drugs that enable weight loss in a short time and without side effects that may put at risk the patient's health.
Initially, the main therapy to be considered is the improvement in the patient's habits, i.e., increasing exercise and having a proper diet. However, when the obesity problem is not solved through this way it requires drug treatment. Most drugs for the treatment of obesity act by decreasing food intake through an appetite suppression mechanism. Such drugs act at the central nervous system (CNS) level and have an anorexigenic effect. For this reason its use is not recommended for long-term treatments.
According to the international consensus, the use of obesity drugs is justified when the diet treatment fails, exercise and behavioral management in patients with BMI>30 Kg/m2 (obese) or BMI>25 Kg/m2 (overweight) and co-morbidity of medical relevance (type 2 diabetes, hypertension, dyslipidemia, arthropathy, and so on).
According to the field of invention, the ideal characteristics of a drug product for the treatment of obesity are:
1. Demonstrated reduction in weight and associated diseases.
2. Tolerable or transient side effects.
3. No major adverse reactions after years of use.
4. Long-term sustained efficacy.
5. Without addictive properties.
6. Known mechanism(s) of action.
7. Affordability.
The drugs used for the treatment of obesity are classified according to their mechanism of action as described below:                Appetite inhibitors or satiety stimulators.        Adrenergic agents: Diethylpropion, Mazindol, Phentermine, Ephedrine.        Selective inhibitors for serotonin uptake: Fluoxetine, Sertraline.        Dual action (adrenergic-serotoninergic): Sibutramine.        Endocannabinoid receptor 1 inhibitors: Rimonabant.        Thermogenics-lipolytics: Ephedrine/Caffeine.        Fat absorption inhibitor or lipase enzyme inhibitor: Orlistat.        Natural products: Resveratrol.        
Active agent orlistat belongs to the group of inhibitors of the lipase enzyme. This compound is an off-white waxy solid, easily soluble in chloroform, insoluble in water, with a melting point between 40° C.-48° C.
Orlistat reduces the absorption of fat by the inhibition of pancreatic lipase activity, avoiding the splitting of fats in their simplest components, provoking their disposal without being absorbed. This compound exerts its therapeutic activity in the lumen of the stomach and in the small intestine, forming a covalent bond with the serine in the active site of the gastric and pancreatic lipases.
Orlistat is administered orally at doses not greater than 360 mg per day, given that higher doses do not have a therapeutic effect. Depending on the patient, different doses may be administered which can be from 30 mg, 60 mg, 120 mg to 240 mg. Different medical publications mention that the usual dose is the administration of 120 mg three times per day.
In obese patients with type 2 diabetes, orlistat is used in weight reduction, and thus it helps to achieve a better glycemic control and reduces postprandial increments of triglycerides, cholesterol and free fatty acids. Orlistat provides additional control when being administered in combination with antidiabetic agents such as metformin, sulfonylureas and/or insulin.
In volunteers with normal weight and obese subjects, the systemic exposure to orlistat is minimal. Plasma concentrations of intact orlistat were virtually undetectable (<5 ng/ml) after single administration of 360 mg. In general, plasma concentrations are extremely low (<10 ng/ml or 0.02 μM) with no evidence of accumulation. Studies in people with normal weight or obese have shown that fecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of the administered dose was excreted in feces and 83% of that was unchanged orlistat.
Orlistat adverse reactions are, largely, of gastrointestinal nature and are related to the pharmacological effect of the drug in the 30% decrease of the absorption of ingested fat. The commonly observed events are grease stains, flatulence and secretions, fecal urgency, grease/oily stools, oily evacuation, increased defecation and fecal incontinence. A higher incidence of these effects has been observed with an increase of fat content in the diet.
Similarly it has been determined a decrease in the absorption of vitamin D, E and β-carotene when they are co-administered with orlistat, but serum levels of these vitamins remained within normal limits.
Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin present in grapes and derived products such as wine, and other foods like oysters, peanuts and nuts. It is a powerful antioxidant, polyphenolic, with a molecular formula C14H12O3 and molecular weight of 228.25. Is a yellowish white powder, non-hygroscopic, insoluble in water, soluble in alcohol and methanol, insoluble in hydrochloric acid 10% and photosensitive. It naturally exists in the form of cis- and trans-isomer, the most common being the trans-resveratrol found in the skin of grapes.
The mechanism of action of this active agent is not yet defined, although some publications mention that it is capable of stimulating the SIRT1 gene family, which codifies sirtuins (NAD-dependent histone deacetylases), triggering metabolic processes related to the duration of life, which are the same that are triggered with restricted diets, thus mimicking caloric restriction. Thus, it is assumed that a low calorie and low carbohydrate diet can extend life. Resveratrol is capable of inhibiting several inflammatory enzymes including cyclooxygenase and lipoxygenase.
In metabolic regulation, resveratrol allows maintaining the effects of a low calorie diet, without changing the food intake, which may be beneficial in the treatment of obesity.
In animal studies, resveratrol exhibits anti-aging effects, cardioprotective effects (in vitro resveratrol inhibits platelet aggregation), neuroprotective effects (by activating SIRT1 it reduces neurodegenerative diseases), anti-inflammatory and chemopreventive effects and as a metabolic regulator it maintains a low calorie diet, without changing the food intake, which may be beneficial in the treatment of obesity.
In humans, although the trans-resveratrol appears to be well absorbed when taken orally, its bioavailability is relatively low due to its rapid metabolism and renal elimination (half-life of approximately 8 h) getting very low levels, both intracellular and in plasma. This active agent is removed in its conjugated forms glucoronate and sulfonate. Studies have shown a polymorphism in the intestinal absorption and in the hepatic metabolism, depending on the species used in the studies.
Various publications have shown that mono-therapy in the treatment of obesity is not effective, combination therapy being indispensable. Nowadays, the literature mentions different combinations for the treatment of obesity and related health problems, however none of them foresees the use of orlistat-resveratrol or provides data on the advantages of this combination or its dosage, clinical trials aren't mentioned either and on the contrary, they warn of adverse effects that may occur.
For example, international patent application WO 2004/080450 describes the use of orlistat with fibrates however, this combination may cause gastrointestinal and skin problems like puritus, rash or photosensitivity.
Patent application WO 2001/000205 describes the combination of sibutramine and orlistat. This combination can represent a risk to patients because sibutramine has been withdrawn from the market by health authorities due to adverse cardiovascular effects it causes.
Mexican patent application No. MX/a/2007/006092 describes the use of orlistat with simvastatin or atorvastatin to decrease the levels of lipids or fatty acids. Combinations herein may develop rhabdomyolysis.
Mexican patent application No. PA/a/2005/013654 shows the combination of orlistat and bupropion. This combination has the disadvantage that the use of bupropion can cause convulsive episodes and adverse effects on the central nervous system of the patient.
The combination of the present application avoids the problems of the combinations mentioned in the prior art. The use of orlistat together with resveratrol has the following advantages:                Anti-obesity effect.        Induced weight loss.        The use of the combination does not require a low caloric intake.        Induced weight loss in shorter treatment times.        It has tolerable side effects or may even have no side effects.        Induction of a better control of blood pressure.        Stimulation of improved glycemic profile.        Induction of a better control of cholesterol and lipid levels.        The combination provides anti-aging and antioxidant effects.        The combination has cardioprotective effect.        The elimination process of each agent is not affected.        The half life of each agent is not affected.        The doses of orlistat or resveratrol used in the combination may be lower than those used in the usual way.        The combination doesn't cause dependence.        The combination modifies positively the desire of food intake.        